The new compounds according to the present invention possess valuable pharmacological properties and, in particular, they increase the strength of the heart and/or have a blood pressure-lowering action and/or influence the thrombocyte aggregation and improve the microcirculation. They are therefore useful to treat coronary insufficiencies, cardiac failure, and blood circulatory disturbances and occlusive diseases.
In the general formulae given hereinafter and especially in the above-given general formula I, the substituents R.sub.1 and R.sub.2 can be the same or different and represent hydrogen atoms, straight-chained or branched alkyl or alkenyl radicals containing up to 6 or containing 2 to 6 carbon atoms, respectively, cyano groups or carbonyl groups substituted by hydroxyl, alkyl, alkoxy, amino, alkylamino, dialkylamino or hydrazino, each of the above-mentioned alkyl moieties being straight-chained or branched and containing up to 6 or 2 to 6 carbon atoms. However, hydrogen atoms and methyl, ethyl, allyl, cyano, carboxyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and hydrazinocarbonyl groups are especially preferred for R.sub.1 and R.sub.2.
If only R.sub.2 represents a hydrogen atom, then R.sub.1 is a straight-chained alkyl radical containing up to 6 carbon atoms or a branched alkyl radical, a cycloalkyl or alkenyl radical containing 3 to 7 carbon atoms, a cyano group or a carbonyl group substituted by alkyl, alkoxy, amino, alkylamino, dialkylamino or hydrazino group. Preferred in this sense are methyl, ethyl, isopropyl, isobutyl, pentyl, cyclopentyl, cyclohexyl, allyl, cyano, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and hydrazinocarbonyl.
R.sub.1 and R.sub.2, together with the carbon atom to which they are attached, can also form a cycloalkyl ring containing 3 to 8 carbon atoms which is preferably a spirocyclopropyl, spirocyclobutyl, spirocyclopentyl or spirocyclohexyl radical.
R.sub.1 and R.sub.2 can together also form a C.sub.2 -C.sub.6 alkylidene or C.sub.3 -C.sub.8 cycloalkylidene radical, the isopropylidene radical thereby being preferred.
Alkyl and alkoxy substituents of the pyridine ring can contain up to 6 and preferably up to 4 carbon atoms, methyl, ethyl, methoxy and ethoxy radicals being preferred. halogen is to be understood to be fluorine, chlorine or bromine, chlorine being preferred.
When Py is a 2-, 3- or 4-pyridyl radical which optionally carries an oxygen atom on the ring heteroatom and/or can be substituted by one or more times by alkyl, alkoxy, hydroxyl, cyano or nitro, as well as by halogen, and x is a valency bond, then Py is preferably a 2-pyridyl, 2-(N-oxypyridyl), 2-(5-n-butylpyridyl), 3-pyridyl, 3-(N-oxypyridyl), 3-(6-methylpyridyl), 3-(6-cyanopyridyl), 3-(6-nitropyridyl), 3-(6-hydroxypyridyl), 3-(2-methoxy-6-methylpyridyl), 4-pyridyl, 4-(N-oxypyridyl), 4-(2-methylpyridyl), 4-(2-ethylpyridyl), 4-(2-hydroxypyridyl), 4-(2-methoxypyridyl), 4-(2-nitroypyridyl), 4-(2-chloropyridyl) or 4-(3-hydroxypyridyl) radical.
When X is a C.sub.1 -C.sub.4 alkylene radical or a vinylene radical and Py represents a 2-, 3- or 4-pyridyl radical, there are especially preferred in this sense 3-pyridylmethyl, 3-pyridylethyl, 3-pyridylvinyl, 4-pyridylmethyl, 4-pyridylethyl and 4-pyridylvinyl radicals.
Preferred pyrrolobenzimidazoles of general formula I are compounds in which R.sub.1 signifies hydrogen, methyl, ethyl, 2-propyl, 2-methylpropyl or cyclopentyl, R.sub.2 signifies hydrogen, methyl, ethyl, ethoxycarbonyl or hydrazinocarbonyl or R.sub.1 and R.sub.2, together with the carbon atom to which they are attached, form a cyclopentane ring or together represent an isopropylidene radical, X signifies a valency bond or a methylene, ethylene or vinylene radical, T signifies an oxygen or sulphur atom and Py signifies a pyridyl-N-oxide radical or a pyridyl radical which can be substituted one or more times by hydroxyl, methoxy, methyl or halogen.
Especially preferred are compounds of general formula I in which T is oxygen, X is a valency bond, R.sub.1 is hydrogen or methyl, R.sub.2 is methyl, ethyl or ethoxycarbonyl and Py is a pyridine-N-oxide radical or a pyridyl radical which can be substituted by hydroxyl or methyl.
The compounds of general formula I can be prepared in one of the following ways:
(a) o-cyanobenzyl nitrile of the formula: ##STR2## is alkylated with a compound of the general formula: EQU R.sub.1 -Z (III)
or with a compound of the general formula: EQU Z-R.sub.3 -Z (IV)
in which R.sub.1 has the same meaning as above, R.sub.3 is a C.sub.2 -C.sub.6 alkylene group and Z is a group which can be split off, to give a compound of the general formula: ##STR3## in which R.sub.1 and R.sub.2 have the same meanings as above, which is subsequently cyclised in an acidic medium to give a compound of the general formula: ##STR4## in which R.sub.1 and R.sub.2 have the same meanings as above, or
(b) isoquinoline-1,3-dione is alkylated with a compound of general formula III or IV to give a compound of the general formula VI, or
(c) isoquinoline-1,3-dione is condensed with a compound of the general formula: ##STR5## in which R.sub.4 and R.sub.5 are hydrogen atoms and/or alkyl radicals or R.sub.4 together with R.sub.5 form a C.sub.3 -C.sub.7 cycloalkylene radical, in the presence of a base to give a compound of the general formula: ##STR6## in which R.sub.4 and R.sub.5 have the same meanings as above, and possibly subsequently compounds of general formula VIII are converted by catalytic hydrogenation into compounds of general formula VI in which R.sub.1 or R.sub.2 is hydrogen.
A group Z which can be split off in general formulae III and IV is, as a rule, a halogen atom, chlorine, bromine and iodine thereby being preferred.
The cyclising of a compound of general formula V takes place in an acidic medium, preferably in the presence of a mineral acid, such as hydrochloric acid or sulphuric acid.
The condensation of isoquinoline-1,3-dione with a compound of general formula VII takes place in the presence of a base, preferably of potassium hydroxide or sodium hydroxide.
The catalytic hydrogenation of compounds of general formula VIII preferably takes place with Pd/C in an alcoholic medium.
Compounds of general formula VI, as well as the preceding process steps, carried out are described in Federal Republic of Germany Patent Application No. P 34 10 168.3.
The compounds so obtained of general formula VI are converted in known manner, by nitration in the 7-position, into compounds of the general formula: ##STR7## in which R.sub.1 and R.sub.2 have the same meanings as above, from which, by Hoffmann reaction with hypohalide according to N. A. Joensson and P. Moses, Acta Chem. Scand., B28, 225-232/1974, there can be obtained compounds of the general formula: ##STR8## in which R.sub.1 and R.sub.2 have the same meanings as above.
By reduction of the nitro group to give an amino group, there are obtained compounds of the general formula: ##STR9## in which R.sub.1 and R.sub.2 have the same meanings as above, which can also be obtained in known manner from appropriately substituted derivatives of 2,4-diaminophenylacetic acid by ring closure (see, in this regard R. C. Elderfield (ed.), P. L. Julian, E. W. Meyer, H. C. Printy, Heterocycl. Comp., Vol. 3, 126-186, pub. John Wiley & Sons, New York, 1952).
The so obtained compounds of general formula XI are converted in known manner, by acetylation of the amino group in the 6-position, nitration in the 5-position, splitting off of the protective group and reduction of the nitro group in the 5-position, into 5,6-diaminoindolin-2-ones of the general formula: ##STR10## in which R.sub.1 and R.sub.2 have the same meanings as above.
The preparation of compounds of general formula I can also take place in the following manner:
(d) compounds of general formula XII are obtained by alkylating an oxindole derivative, protected on the nitrogen atom, of the general formula: ##STR11## in which R.sub.1 and R.sub.2 are hydrogen atoms and A is a protective group, for example an acetyl or benzyl protective group, with compounds of general formulae III or IV with the above given meanings to give other compounds of general formula XIII in which R.sub.1 and R.sub.2 have the above-given meanings, except that R.sub.1 and R.sub.2 are not hydrogen atoms. After splitting off a benzyl protective group, for example by sodium in liquid ammonia, or of an acetyl protective group in an acidic or basic medium, there is obtained an indolin-2-one of general formula XIII in which A is a hydrogen atom and R.sub.1 and R.sub.2 have the above-given meanings, except that R.sub.1 and R.sub.2 are not hydrogen atoms.
The so obtained compounds of general formula XIII are converted in known manner, by nitration in the 5-position, subsequent reduction of the nitro group to an amino group, acetylation of the amino group in the 5-position, nitration in the 6-position, splitting off of the protective group and reduction of the nitro group in the 5-position, into corresponding 5,6-diaminoindolin-2-one derivatives of general formula XII with the above-given definitions.
The process according to the present invention for the preparation of compounds of general formula I takes place by reacting compounds of general formula XII with compounds of the general formula: EQU Py--X--CO--Y (XIV)
in which Py and X have the above-given meanings and Y is either a hydrogen atom or a radical which can easily be split off, and the compounds obtained are cyclised to give compounds of general formula I or a tautomeric form thereof and compounds obtained according to the present invention of general formula I are, if desired, converted into other compounds of general formula I or tautomers thereof and/or compounds obtained of general formula I and the tautomers thereof are converted into physiologically acceptable acid addition salts with inorganic or organic acids.
By compounds of general formula XIV, there are to be understood, in particular, aldehydes, as well as acid halides, such as acid chlorides, carboxylic acid esters, such as methyl and ethyl esters, and other activated carboxylic acid derivatives, for example anhydrides.
If the compound of general formula XIV is an aldehyde, the reaction to give a Schiff's base takes place with a compound of general formula XII, preferably in an alcoholic medium, the subsequent cyclisation and oxidation to give a compound of general formula I taking place by warming the reaction mixture to reflux in the presence of atmospheric oxygen and a catalytic amount of an acid, for example toluence-sulphonic acid.
If the compound of general formula XIV is a carboxylic acid derivative, the reaction with a compound of general formula XII to give an amide takes place in an inert solvent, preferably in methylene chloride, and the subsequent cyclisation to give a compound of general formula I is carried out in an acidic medium, preferably in the presence of a mineral acid, for example sulphuric acid or hydrochloric acid, in an alcoholic solution.
Compounds of general formula I are also obtained
(e) by starting with compounds of the general formula: ##STR12## or of the general formula: ##STR13## in which R.sub.1, R.sub.2 and T have the same meanings as above, by reacting with compounds of the general formula XIV, in which Y is a residue which can easily be split off, to give compounds of the general formula: ##STR14## or compounds of the general formula: ##STR15## in which R.sub.1, R.sub.2, T, Py and X have the same meanings as above, which are converted in known manner by nitration into compounds of the general formula: ##STR16## or of the general formula: ##STR17## in which R.sub.1, R.sub.2, T, Py and X have the same meanings as above.
After hydrogenation of the compounds of general formulae XIX and XX to give the corresponding amino compounds of the general formula: ##STR18## or of the general formula: ##STR19## in which R.sub.1, R.sub.2, T, Py and X have the same meanings as above, there are obtained, by cyclisation, the desired compounds of general formula I.
Compounds of general formula XVI are obtained, for example, by nitration of compounds of the general formula: ##STR20## in which R.sub.1, R.sub.2 and T have the same meanings as above, in the 5-position and subsequent reduction of the nitro group to an amino group.
The preparation of compounds of general formula I can also take place in the following manner:
(f) compounds of general formulae XV or XVI are acetylated on to 6- or 5-amino function in generally known manner and, by subsequent nitration and splitting off of the acetyl protective groups, there are obtained compounds of the general formula: ##STR21## or of the general formula: ##STR22## in which R.sub.1, R.sub.2 and T have the same meanings as above. By reaction with compounds of general formula XIV, there are also obtained, in the above-described manner, compounds of general formula XIX or XX.
(g) Compounds of general formula I or their tautomeric forms, as well as the intermediate products leading to them, can, apart from the above-described processes, also be prepared by various processes known from the literature, for example from compounds of the general formula: ##STR23## in which Py and X have the above-given meanings (see, in this regard, R. C. Elderfield (ed.), P. L. Julian, E. W. Meyer, H. C. Printy, Heterocycl. Comp., Vol. 3, 126-186, 1952, pub. John Wiley & Sons, New York).
Thus, for example, a compound of general formula XXVI is acylated with a reactive derivative of a carboxylic acid of the general formula: ##STR24## preferably an acid chloride, and cyclised with a Lewis acid (aluminum chloride) (Stollesynthesis), in which Hal can be chlorine, bromine or iodine and R.sub.1 and R.sub.2 have the same meanings as above. The 7-monosubstituted compounds of general formula I can preferably be prepared by this method.
According to another variant, compounds of the general formula: ##STR25## are reacted with a reactive derivative of a carboxylic acid of the general formula: ##STR26## preferably an acid chloride, in which R.sub.1 and R.sub.2 have the above-given meanings, to give corresponding hydrazides and these are then cyclised under alkaline conditions (Brunner synthesis).
Reactive carboxylic acid derivatives of general formulae XXVII and XXIX are especially acid chlorides, anhydrides and mesyl and tosyl esters.
Corresponding compounds of general formula I or the intermediate products leading thereto can also be obtained by reacting phenyl hydraine or appropriately substituted phenyl hydrazines in the manner described by K. Brunner (Monatsh. f. Chemie, 18, 95/1897) or, for example, by alkylating 2,4-dinitrochlorobenzene with appropriately substituted malonic acid derivatives, for example the sodium salt of methylmalonic acid diethyl ester, by processes known from the literature, subsequent reduction of the nitro groups and ring closure to give comnpounds of general formula XV.
The above-mentioned hydrogenation of a nitro group in the processes described under (a) to (g) to give compounds of general formula I is preferably carried out in a solvent or solvent mixture, for example water, ethanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a catalyst, such as Raney nickel, platinum or palladium/charcoal, with metals, such as iron, tin or zinc, in the presence of an acid, with salts, such as ferrous sulphate, stannous chloride, sodium sulphide, sodium hydrogen sulphide or sodium dithionite, or with hydrazine in the presence of Raney nickel at a temperature of from 0.degree. to 100.degree. C. but preferably at ambient temperature.
The cyclisations mentioned above in processes (a) to (g) to give the desired compounds of general formula I are preferably carried out in a solvent or solvent mixture, for example ethanol, isopropanol, glacial acetic acid, benzene, toluene, chlorobenzene, glycol, ethylene glycol dimethyl ether, sulfolane or dimethylformamide, at a temperature of from 0.degree. to 220.degree. C. but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensation agent, for example, phosphorus oxychloride, thionyl chloride, p-toluenesulphonic acid, hydrochloric acid, sulphuric acid, phosphoric acid or polyphosphoric acid, or possibly also in the presence of a base, for example, sodium hydroxide, sodium methylate or potassium tert.-butylate. However, the cyclisation can also be carried out without the use of solvents and/or of condensation agents.
The subsequent conversion of a compound of generally formula I into another compound of general formula I is concerned, for example, with the oxidation of the pyridyl radical into the corresponding N-oxide, which mainly takes place with hydrogen peroxide in acetic acid, as well as the hydrogenation of an unsaturated substituent. This applies especially to the hydrogenation of a vinyl compound (X=--CH.dbd.CH--) to give the corresponding ethyl compound.
The subsequent conversion of a compound of general formula I, in which R.sub.1 and R.sub.2 are hydrogen atoms, into another compound of general formula I is, for example, also concerned with the reaction of a compound of general formula VII with the above-given meaning in the presence of a base, such as ammonia or triethylamine, in alcoholic solution. In particular, this concerns the conversion of compounds of general formula I in which R.sub.1 and R.sub.2 are hydrogen atoms into compounds of general formula I in which R.sub.1, together with R.sub.2, represent an isopropylidene group, a cyclopentylidene group or a cyclohexylidene group, as well as possibly the hydrogenation thereof to give the corresponding compounds of general formula I in which R.sub.1 or R.sub.2 is hydrogen.
Furthermore, the subsequent conversion of compounds of general formula I in which R.sub.1 or R.sub.2 is a carboxyl group or a reactive derivative thereof, for example a carboxylic acid ester or acid chloride, is concerned with the reaction with hydrazine, ammonia, a primary or secondary amine or a reactive derivative thereof to give new compounds of general formula I, in which R.sub.1 or R.sub.2 is a carbonyl group substituted by an amino, alkylamino, dialkylamino or hydrazino group. The subsequent conversion also concerns compounds of general formula I in which R.sub.1 or R.sub.2 is an aminocarbonyl group to give those in which R.sub.1 or R.sub.2 is a cyano group, as well as the subsequent conversion of a cyano group into a carboxyl, aminocarbonyl or alkoxycarbonyl group. These conversions are all carried out by methods which are generally used and are known from the literature.
The subsequent conversion to compounds of general formula I and to intermediate products leading to compounds of general formula I in which T is a sulphur atom from those in which T is an oxygen atom is carried out by processes known from the literature with a reagent transmitting the sulphur atom, for example phosphorus pentasulphide or 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane, in an appropriate solvent, for example tetrahydrofuran, dioxan, ethylene glycol dimethyl ether, benzene, toluene or pyridine, at a temperature of from 0.degree. C. to the boiling temperature of the reaction mixture.
The compounds of general formula XII, XIX, XX, XXIV and XXV in which R.sub.1 is a hydrogen atom or an alkyl, alkenyl or a cycloalkyl radical and R.sub.2 is a hydrogen atom, an alkyl, alkenyl or cyano group, a carbonyl group substituted by a hydroxyl, alkyl, alkoxy, amino, alkylamino, dialkylamino or hydrazino group or forms a cycloalkylene group with R.sub.1 and, so far as is relevant, X is a valency bond, a C.sub.1 -C.sub.4 alkylene group or a vinyl radical, T is an oxygen or sulphur atom and Py is a 2-, 3- or 4-pyridyl radical which can possibly be substituted one or more times by alkyl, alkoxy, hydroxyl, cyano or nitro, as well as by halogen, are new an also the subject of the present invention.
Compounds according to the present invention of general formula XII are, apart from those mentioned in the Examples, also the following compounds:
5,6-diamino-3-acetylindolin-2-one PA1 5,6-diamino-3-acetyl-3-methylindolin-2-one PA1 5,6-diamino-3-allylindolin-2-one PA1 5,6-diamino-3-cyano-3-methylindolin-2-one PA1 5,6-diamino-3-cyclohexylindolin-2-one PA1 5,6-diamino-3-cyclopentylindolin-2-one PA1 5,6-diamino-3,3-diallylindolin-2-one PA1 5,6-diamino-3-ethoxycarbonylindolin-2-one PA1 5,6-diamino-3-ethoxycarbonyl-3-ethylindolin-2-one PA1 5,6-diamino-3-ethoxycarbonyl-3-methylindolin-2-one PA1 5,6-diamino-3-ethylindolin-2-one PA1 5,6-diamino-3-methoxycarbonylindolin-2-one PA1 5,6-diamino-3-methoxycarbonyl-3-methylindolin-2-one PA1 5,6-diamono-3-methylindolin-2-one PA1 5,6-diamino-3-(3-pentyl)-indolin-2-one PA1 5,6-diamino-3-(2-propyl)-indolin-2-one PA1 5,40 ,6'-diamino-spiro[cyclohexane-1,3'-indolin]-2'-one. PA1 5-amino-6-nitro-3-acetylindolin-2-one PA1 5-amino-6-nitro-3-actyl-3-methylindolin-2-one PA1 5-amino-6-nitro-3-allylindolin-2-one PA1 5-amino-6-nitro-3-cyano-3-methylindolin-2-one PA1 5-amino-6-nitro-3-cyclohexylindolin-2-one PA1 5-amino-6-nitro-3-cyclopentylindolin-2-one PA1 5-amino-6-nitro-3,3-diallylindolin-2-one PA1 5-amino-6-nitro-3-ethoxycarbonylindolin-2-one PA1 5-amino-6-nitro-3-ethoxycarbonyl-3-ethylindolin-2-one PA1 5-amino-6-nitro-3-ethoxycarbonyl-3-methylindolin-2-one PA1 5-amino-6-nitro-3-ethylindolin-2-one PA1 5-amino-6-nitro-3-methoxycarbonylindolin-2-one PA1 5-amino-6-nitro-3-methoxycarbonyl-3-methylindolin-2-one PA1 5-amino-6-nitro-3-methylindolin-2-one PA1 5-amino-6-nitro-3-(3-pentyl)-indolin-2-one PA1 5-amino-6-nitro-3-(2-propyl)-indolin-2-one PA1 5-amino-6-nitro-3-(2-methylpropyl)-indolin-2-one PA1 5'-amino-6'-nitrospiro[cyclohexane-1,3'-indolin]-2'-one PA1 5'-amino-6'-nitrospiro[cyclopentane-1,3'-indolin]-2'-one PA1 5-amino6-nitro-3,3-dimethylindolin-2-thione PA1 5-amino-6-nitro-3-ethylindolin-2-thione PA1 5-amino-6-nitro-3-methylindolin-2-thione. PA1 6-amino-5-nitroindolin-2-one PA1 6-amino-5-nitro-3-acetylindolin-2-one PA1 6-amino-5-nitro-3-acetyl-3-methylindolin-2-one PA1 6-amino-5-nitro-3-allylindolin-2-one PA1 6-amino-5-nitro-3-cyano-3-methylindolin-2-one PA1 6-amino-5-nitro-3-cyclohexylindolin-2-one PA1 6-amino-5-nitro-3-cyclopentylindolin-2-one PA1 6-amino-5-nitro-3,3-diallylindolin-2-one PA1 6-amino-5-nitro-3-ethoxycarbonylindolin-2-one PA1 6-amino-5-nitro-3-ethoxycarbonyl-3-ethylindolin-2-one PA1 6-amino-5-nitro-3-ethoxycarbonyl-3-methylindolin-2-one PA1 6-amino-5-nitro-3-ethylindolin-2-one PA1 6-amino-5-nitro-3-methoxycarbonylindolin-2-one PA1 6-amino-5-nitro-3-methoxycarbonyl-3-methylindolin-2-one PA1 6-amino-5-nitro-3-methylindolin-2-one PA1 6-amino-5-nitro-3-(3-pentyl)-indolin-2-one PA1 6-amino-5-nitro-3-(2-propyl)-indolin-2-one PA1 6'-amino-5'-nitrospiro[cyclohexane-1,3'-indolin]-2'-one PA1 6-amino-5-nitro-3,3-dimethylindolin-2-thione PA1 6-amino-5-nitro-3-ethylindolin-2-thione PA1 6-amino-5-nitro-3-methylindolin-2-thione. PA1 5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-acetyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-acetyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-acetyl-3-methyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-allyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-allyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-cyano-3-methyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-cyano-3-methyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-cyclohexyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-cyclohexyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-cyclopentyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3,3-diallyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3,3-diallyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3,3dimethyl-5-nitro-6-(2-pyridinoylamino)-indolin-2-one PA1 3,3-dimethyl-5-nitro-6-[2-(5-n-butylpyridinoylamino)]-indolin-2-one PA1 3,3-dimethyl-5-nitro-6-[3-(6-cyanopyridinoylamino)]-indolin-2-one PA1 3,3-dimethyl-5-nitro-6-[3-(6-methylpyridinoylamino)]-indolin-2-one PA1 3,3-dimethyl-5-nitro-6-[4-(2-methylpyridinoylamino)]-indolin-2-one PA1 3-ethoxycarbonyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-3-ethyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-3-ethyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-3-methyl-5-nitro-6-(3-pyridnoylamino)-indolin-2-one PA1 3-methoxycarbonyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-methoxycarbonyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-methoxycarbonyl-3-methyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-methoxycarbonyl-3-methyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-(3-pentyl)-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-(3-pentyl)-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 3-(2-propyl)-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-(2-methylpropyl)-5-nitro-6-(3-pyridinoylamino)-indolin-2-one PA1 3-(2-methylpropyl)-5-nitro-6-(4-pyridinoylamino)-indolin-2-one PA1 5'-nitro-6'-(3-pyridinoylamino)-spiro[cyclohexane-1,3'-indolin]-2'-one PA1 5'-nitro-6'-(4-pyridinoylamino)-spiro[cyclohexane-1,3'-indolin]-2'-one PA1 5'-nitro-6'-(3-pyridinoylamino)-spiro[cyclopentane-1,3'-indolin]-2'-one PA1 5'-nitro-6'-(4-pyridinoylamino)-spiro[cyclopentane-1,3'-indolin]-2'-one PA1 3,3-dimethyl-5-nitro-6-(2-pyridinoylamino)-indolin-2-thione PA1 3,3-dimethyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-thione PA1 3,3-dimethyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-thione PA1 3-ethyl-5-nitro-6-(2-pyridinoylamino)-indolin-2-thione PA1 3-ethyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-thione PA1 3-ethyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-thione PA1 3-methyl-5-nitro-6-(2-pyridinoylamino)-indolin-2-thione PA1 3-methyl-5-nitro-6-(3-pyridinoylamino)-indolin-2-thione PA1 3-methyl-5-nitro-6-(4-pyridinoylamino)-indolin-2-thione. PA1 6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-acetyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-acetyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-acetyl-3-methyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-acetyl-3-methyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-allyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-allyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-cyano-3-methyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-cyano-3-methyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-cyclohexyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-cyclohexyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-cyclopentyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-cyclopentyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3,3-diallyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3,3-diallyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3,3-diethyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3,3-diethyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3,3-dimethyl-6-nitro-5-(2-pyridinoylamino)-indolin-2-one PA1 3,3-dimethyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3,3-dimethyl-6-nitro-5-[2-(5-n-butylpyridinoylamino)]-indolin-2-one PA1 3,3-dimethyl-6-nitro-5-[3-(6-cyanopyridinoylamino)]-indolin-2-one PA1 3,3-dimethyl-6-nitro-5-[3-(6-methylpyridinoylamino)]-indolin-2-one PA1 3,3-dimethyl-6-nitro-5-[4-(2-methylpyridinoylamino)]-indolin-2-one PA1 3,3-dimethyl-6-nitro-5-[4-(2-hydroxypyridinoylamino)]-indolin-2-one PA1 3-ethoxycarbonyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-3-ethyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-3-ethyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-3-methyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-ethoxycarbonyl-3-methyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-ethyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-ethyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-methoxycarbonyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-methoxycarbonyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-methoxycarbonyl-3-methyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-methoxycarbonyl-3-methyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-methyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-methyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-(3-pentyl)-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-(3-pentyl)-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-(2-propyl)-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-(2-propyl)-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 3-(2-methylpropyl)-6-nitro-5-(3-pyridinoylamino)-indolin-2-one PA1 3-(2-methylpropyl)-6-nitro-5-(4-pyridinoylamino)-indolin-2-one PA1 6'-nitro-5'-(3-pyridinoylamino)-spiro[cyclohexane-1,3'-indolin]-2'-one PA1 6'-nitro-5'-(4-pyridinoylamino)-spiro[cyclohexane-1,3'-indolin]-2'-one PA1 6'-nitro-5'-(3-pyridinoylamino)-spiro[cyclopentane-1,3'-indolin]-2'-one PA1 6'-nitro-5'(4-pyridinoylamino)-spiro[cyclopentane-1,3'-indolin]-2'-one PA1 3,3-dimethyl-6-nitro-5-(2-pyridinoylamino)-indolin-2-thione PA1 3,3-dimethyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-thione PA1 3,3-dimethyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-thione PA1 3-ethyl-6-nitro-5-(2-pyridinoylamino)-indolin-2-thione PA1 3-ethyl-6-nitro-5-(3-pyridinoylamino)-indolin-2-thione PA1 3-ethyl-6-nitro-5-(4-pyridinoylamino)-indolin-2-thione PA1 3-methyl -6-nitro-5-(2-pyridinoylamino)-indolin-2-thione PA1 3-methyl -6-nitro-5-(3-pyridinoylamino)-indolin-2-thione PA1 3-methyl -6-nitro-5-(4-pyridinoylamino)-indolin-2-thione. PA1 2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one PA1 7-acetyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one PA1 7-acetyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one PA1 7-acetyl-7-methyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazo l-6-one PA1 7-acetyl-7-methyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazo l-6-one PA1 7-allyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one PA1 7-allyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one PA1 7-aminocarbonyl-7methyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzi midazol-6-one PA1 7-aminocarbonyl-7methyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzi midazol-6-one PA1 7-cyano-7methyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol- 6-one PA1 7-cyano-7methyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol- 6-one PA1 7-cyclohexyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-o ne PA1 7-cyclohexyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-o ne PA1 7-cyclopentyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6- one PA1 7,7-diallyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-on e PA1 7,7-diallyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-on e PA1 7,7-diethyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-on e PA1 7,7-diethyl-2-(4-N-oxypyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol -6-one PA1 7,7-diethyl-2-(4-(2-methylpyridyl))-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimi dazol-6-one PA1 7,7-diethyl-2-(4-pyridylethyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol -6-one PA1 7,7-dimethyl-2-(2N-oxypyridyl)-6,7-dihydro-3H,5-pyrrolo[2,3-f]benzimidazol- 6-one PA1 7,7-dimethyl-2-[2-(5-n-butylpyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzi midazol-6-one PA1 7,7dimethyl-2-[3-(6cyanopyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3,-f]benzimid azol-6-one PA1 7,7-dimethyl-2-[3-(6-hydroxypyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3,-f]benz imidazol-6-one PA1 7,7-dimethyl-2-[3-(6-nitropyridyl)]-6,7dihydro-3H,5H-pyrrolo[2,3,-f]benzimi dazol-6-one PA1 7,7-dimethyl-2-[4-(2-ethylpyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimi dazol-6-one PA1 7,7-dimethyl-2-[4-(2-methoxypyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzi midazol-6-one PA1 7,7-dimethyl-2-[4-(2-nitropyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimi dazol-6-one PA1 7,7-dimethyl-2-(3-pyridylmethyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidaz ol-6-one PA1 7,7-dimethyl-2-(3-pyridylethyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazo l-6-one PA1 7,7-dimethyl-2-(4-pyridylvinyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazo l-6-one PA1 7-ethoxygarbonyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol -6-one PA1 7-ethoxycarbonyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol -6-one PA1 7-ethoxycarbonyl-7-ethyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benz imidazol-6-one PA1 7-ethoxycarbonyl-7-ethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benz imidazol-6-one PA1 7-ethoxycarbonyl-7methyl-2-(3-pyridyl)6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzi midazol-6-one PA1 7-ethyl-2-(3-N-oxypyridyl)-6,7-dihydro-3H,5H-pyrrolo-[2,3-f]benzimidazol-6- one PA1 7-ethyl-2-(4-N-oxypyridyl)-6,7-dihydro-3H,5H-pyrrolo-[2,3-f]benzimidazol-6- one PA1 7-hydrazinocarbonyl-7methyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]b enzimidazol-6-one PA1 7-isopropylidene-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol -6-one PA1 7-methoxycarbonyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazo l-6-one PA1 7-methoxycarbonyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazo l-6-one PA1 7-methoxycarbonyl-7methyl-2-(3-pyridyl)6,7-dihydro-3H,5H-pyrrolo[2,3-f]benz imidazol-6-one PA1 7-methoxycarbonyl-7-methyl-2-(4-pyridyl-6,7-dihydro-3H,5H-pyrrolo[2,3-f]ben zimidazol-6-one PA1 7-methyl-2-(3-N-oxypyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3,-f]benzimidazol-6 -one PA1 7-(2-methylpropyl)-2-(3-pyridyl)-6,7-dihydro-3H,5-pyrrolo[2,3,-f]benzimidaz ol-6-one PA1 7-(2-methylpropyl)-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidaz ol-6-one PA1 7-(3-pentyl)-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-o ne PA1 7-(3-pentyl)-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-o ne PA1 7-(2-propyl)-2-(3-pyridyl)-6,7-dihydro-3H5H-pyrrolo[2,3-f]benzimidazol-6-on e PA1 7-(2-propyl)-2-[4-(2-methylpyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzim idazol-6-one PA1 2'-(3-pyridyl)-spiro]cyclopropane-1,7'-6',7'-dihydro-3'H,5'H-pyrrolo[2',3'- f]benzimidazol]-6'-one PA1 2'-(3-pyridyl)-spiro[cyclopentane-1,7'-6',7'-dihydro-3'H,5'H-pyrrolo[2',3'- f]benzimidazol]-6'-one PA1 2'-(3-pyridyl)-spiro[cyclohexane-1,7'-6',7'-dihydro-3'H,5'H-pyrrolo[2',3'-f ]benzimidazol]-6'-one PA1 2'-(4-pyridyl)-spiro[cyclohexane-1,7'-6',7'-dihydro-3'H,5'H-pyrrolo[2',3'-f ]benzimidazol]-6'-one PA1 7,7-dimethyl-2-(2-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-t hione PA1 7,7-dimethyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-t hione PA1 7,7-dimethyl-2-[3-(6-methylpyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzim idazol-6-thione PA1 7,7-dimethyl-2-[4-(2-methylpyridyl)]-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzim idazol-6-thione PA1 7-ethyl-2-(2-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-thione PA1 7-ethyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-thione PA1 7-ethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-thione PA1 7-methyl-2-(2-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-thion e PA1 7-methyl-2-(3-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-thion e PA1 7-methyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-thion e.
Compounds according to the present invention of general formula XXV are, apart from those mentioned in the Examples, also the following compounds:
Compounds according to the present invention of general formula XXIV are, apart from those mentioned in the Examples, also the following compounds:
Compounds according to the present invention of general formula XIX are, apart from those mentioned in the Examples, also the following compounds:
3,3-dimethyl-5-nitro-6-[4-(2-hydroxypyridinoylamino)]-indolin-2-one
Compounds according to the present invention of general formula XX are, apart from those mentioned in the Examples, also the following compounds:
For the conversion of compounds of general formula I or of their tautomeric forms into their pharmacologically acceptable salts, these are reacted, preferably in an organic solvent, with the equivalent amount of an inorganic or organic acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, benzoic acid or cyclohexylsulphaminic acid.
For the preparation of medicaments, the compounds of general formula I are mixed in known manner with appropriate pharmaceutical carrier substances, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, are suspended or dissolved in water or an oil, for example olive oil.
The new compounds of general formula I according to the present invention and their salts can be administered enterally or parenterally in liquid or solid form. As injection medium, it is preferable to use water which contains the additives usual in the case of injection solutions, such as stabilising agents, solubilising agents or buffers.
Such additives are, for example, tartrate and citrate buffers, ethanol, complex formers (such as ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening agents.
The compounds of general formula I according to the present invention are usually administered in amounts of from 10 to 500 mg. per day, referred to a body weight of 75 kg. It is preferred to administer 2 to 3 times a day 1 to 2 tablets with an active material content of from 5 to 200 mg. The tablets can also be retarded, whereby 1 to 2 tablets containing 10 to 500 mg. of active material need be given only once per day. The active material can also be administered by injection 1 to 8 times per day or by continuous infusion, amounts of from 5 to 200 mg. per day normally being sufficient.
Preferred compounds according to the present invention are, apart from those mentioned in the Examples, also the following compounds and the tautomers thereof: